Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Normal pressure hydrocephalus as an unusual presentation of supratentorial extraventricular space-occupying processes: report on two cases.

Normal pressure hydrocephalus (NPH) is a clinical and radiographic syndrome characterized by ventriculomegaly, abnormal gait, urinary incontinence, and dementia. The condition may occur due to a variety of secondary causes but may be idiopathic in approximately 50% of patients. Secondary causes may include head injury, subarachnoid hemorrhage, meningitis, and central nervous system tumor. Here, we describe two extremely rare cases of supratentorial extraventricular space-occupying processes: meningioma and glioblastoma multiforme, which initially presented with NPH.

[Neuropsychological impairment in the early Alzheimer's disease]. / Le déficit neuropsychologique dans la maladie d'Alzheimer débutante.

This analysis is centered on the study of cognitive disorders in Alzheimer's disease (AD), mainly for major neuro-psychological functions. We insist on the heterogeneity of the clinical picture peculiarly in the early stages of the illness, even if the deficits of episodic memory and of attentional/executive capacities are the first to deteriorate, preceding impairment in perceptual and language function and potentially having a substantial impact on the patient's capacity to cope independently. An episodic memory deficit is the hallmark of AD, but it must be stressed that this deficit may take different forms and its origin may be traced back to different cognitive mechanisms. One of the most striking aspects of episodic memory impairment in AD is the rapidity of forgetfulness on which screening and diagnostic tests of AD are based. There is some evidence that the episodic memory deficit in AD is one of learning (encoding and storage) of information rather than to a deficit of retrieval. Furthermore, episodic memory performance in AD depends on the integrity of semantic memory abilities, so giving support to a hierarchical model of organization of human memory. Finally, recent results show that an impairment of conscious recollection is responsible for the poor performance of AD patients in recognition memory. Executive deficits appear predominantly in tasks requiring cognitive flexibility and self-monitoring. With the progression of the disease, additional deficits are observed in the verbal concept formation abilities. These findings might be also very useful in the differential diagnosis between AD and the other cortical and subcortical dementias, as well as in the differentiation between AD and fronto-temporal dementia. We consider that studying early stages of the illness is necessary to delineate the diagnostic signs, to validate the new therapeutic experiments, to predict stages of decline. Recent research suggested that onset of AD is commonly preceded by an interim phase known as mild cognitive impairment (MCI). MCI refers to the clinical condition in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. Persons who experience this condition are at increased risk for the development of AD. In MCI, despite the comparable global cognitive functioning, the findings show more impaired retrieval from long-term storage than in NC. The cued recall improves slightly the total recall but the recognition is significantly impaired. Moreover, the data indicate that MCI patients had additional problems with response inhibition, switching and cognitive flexibility. This suggests, that MCI may be identified by using a more detailed procedure for the assessment of cognitive decline than the evaluation of memory alone. As preventive strategies are developed and new cognitive enhancing therapies emerge, these results may also help us to define which domains are expected to improve in MCI populations.

[Place and role of neuropsychological exam in elderly depression]. / Place et intérêt de l'examen neuropsychologique dans la dépression du sujet âgé.

PURPOSE: Neuropsychology provides essential information to all participants (physicians, psychologists, occupational therapists) involved in the treatment of the elderly. When treating depressed elderly patients, a comprehensive neuropsychological examination is required for diagnosis, prognosis and to control the effectiveness of antidepressant treatment. KEY MESSAGE AND RECENT FACTS: Depression in elderly people is frequent and difficult to diagnose. Some forms of depression usher in or are associated with a neurodegenerative disease. In the case of diagnosis, the neuropsychological examination should furnish useful information to guide the clinician. The qualitative analysis of results (strategies used and type of errors) and the weakening of cognitive processes efficiency provides supplementary information and increases the reliability of the diagnosis. It also gives information about the long term evolution of cognitive deficits. It should reveal the presence of characteristics which help to distinguish patients who are developing dementia (predictive power of certain tests). Finally, it enables the clinician to evaluate the outcome of antidepressant treatment, to adjust the prescription according to the performance and to adapt an holistic treatment. PERSPECTIVE AND PROJECTS: A neuropsychological examination may provide new perspectives, such as the possibility of predicting the outcome of dementia which are accompanied by affective disorders, such as Alzheimer's disease, vascular dementia and frontotemporal dementia. Neuropsychology may thus improve the treatment of these patients by providing information to a better understanding of their deficits and their impact on daily living abilities.

Donepezil for the treatment of mild to moderate Alzheimer's disease in France: the economic implications.

In the present study, the socioeconomic impact of the use of the acetylcholinesterase inhibitor donepezil in patients with mild to moderate Alzheimer's disease (AD) living in France was examined. A model was created to extrapolate over a 3-year period the results from placebo-controlled trials together with epidemiological and prevalence data. Costs considered in the model were net societal costs associated with paid and unpaid assistance, general medical consumption and institutional care. The model suggested that delays in cognitive decline and functional dependence due to treatment reduced the time spent in institutional care and the burden on caregivers. Over a 3-year period, total net costs of caring for untreated patients with an initial Mini-Mental State Examination score ranging from 10 to 26 were EUR 53,206 compared with EUR 42,720 for a patient treated with donepezil--an annual cost saving of approximately EUR 3,500 per patient. Cost savings were mainly due to savings in unpaid caregiver time, which, apart from patient institutionalization, represented the most costly component of total care in this study but had no direct budgetary impact. Overall, these data suggest that donepezil is a cost-effective treatment for mild to moderately impaired AD patients living in France.

[Cognitive decline and hypertension]. / Déclin cognitif et hypertension artérielle.

The prevalence and incidence of degenerative and vascular dementia increase exponentially with age. Several studies in recent years have implicated hypertension as a risk factor not only for vascular dementia but also for degenerative dementia such as Alzheimer's disease. This is an important finding because it suggests that the treatment of hypertension could reduce the incidence of dementia. In particular, the results of the Syst-Eur study, showing that a calcium inhibitor, nitrendipine, could reduce not only the incidence of stroke but also that of dementia, should be confirmed.

Association of the apolipoprotein E epsilon4 allele with late-onset depression.

Apolipoprotein E (ApoE) phenotyping was determined in 42 subjects with Alzheimer's disease (AD), 49 with depression, including 26 with early-onset depression (EOD) and 23 with late-onset depression (LOD), and 49 controls. In the EOD group, the frequency of the ApoE epsilon4 allele was not different from the control frequency (p = 0.532) but was significantly lower than in AD (p < 0.001). In the LOD group, the ApoE epsilon4 frequency was significantly higher than in the controls (p = 0.034) but was not different from that in the AD group (p = 0.229). Individuals with ApoE epsilon4 were at greater risk of getting AD (odds ratio, OR = 5.5, 95% confidence interval, CI, 2.0-14.0) or LOD (OR = 6.1, 95% CI, 1.9-19.0) than of EOD (OR = 0.7, 95% CI, 0.2-2.5). These results suggest an association between the ApoE epsilon4 allele frequency and LOD. Patients with LOD could be at risk of developing AD by an epsilon4-dependent pathway.

The apolipoprotein E epsilon4 allele and the response to tacrine therapy in Alzheimer's disease.

The objective of our study was to evaluate the effects of the apolipoprotein E (ApoE) phenotype and gender on the response to tacrine treatment in Alzheimer's disease (AD). ApoE phenotyping was performed on 76 patients treated with tacrine for AD. This group comprised 33 ApoE epsilon4 allele carriers (epsilon4+) and 43 non-epsilon4 carriers (epsilon4-). Patients were treated blindly in relation to the ApoE phenotype, with incremental tacrine dosages ranging from 40 mg/day up to the highest dosage (160 mg) tolerated without side-effects. At least 6 weeks elapsed between each increase. Changes in the scores for the Alzheimer Disease Assessment Scale-Cognitive Component (ADAS-Cog) between baseline and each increment in dosage were assessed in the epsilon4- and epsilon4+ groups. The cut-off point for being considered as responsive to tacrine treatment was a 4-point decrease in the ADAS-Cog score. There was no tendency for the epsilon4- carriers to respond better than the epsilon4+ carriers. When patients were stratified by gender, no differences were found between the effects of the treatment on men and women. Consequently, these results do not support the hypothesis that the ApoE phenotype and gender are predictors of the response to tacrine in AD patients.

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease.

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).

In vivo PET study of cerebral [11C] methyl- tetrahydroaminoacridine distribution and kinetics in healthy human subjects.

It is unclear whether the palliative effects of tetrahydroaminoacridine (THA) (tacrine, Cognex) on the clinical symptoms of patients affected by Alzheimer's disease (AD) are the result of its inhibitory activity on acetylcholinesterase or on other complex sites of action. In order to investigate the cerebral distribution and kinetics of THA in the human brain in vivo, we performed positron emission tomography (PET) imaging with [11C]N-methyl-tetrahydro-aminoacridine (MTHA) in healthy human volunteers. After intravenous injection, [11C]MTHA crossed the blood-brain barrier and reached its maximum uptake between 10 and 40 minutes, depending on the brain regions. Uptake was higher in the grey matter structures, and lower in the white matter. After this peak, the radioactivity remained quasi- constant until 60 minutes in all regions with a half-life varying from 2.44 hours in the thalamus to 3.42 hours in the cerebral cortex. The ratios of regional to whole cerebral cortex brain radioactivity calculated between 50 and 70 minutes after the tracer injection were 1.14 +/- 0.04, 1.07 +/- 0. 03 and 1.06 +/- 0.04 in the putamen, cerebellum and thalamus, respectively. Overall, these results show that: (1) [11C]MTHA crosses the blood-brain barrier easily and is highly concentrated in the brain; (2) the regional brain distribution of [11C]MTHA does not parallel that of in vivo acetylcholinesterase (AChE) concentrations; and (3) the cerebral kinetics of [11C]MTHA are consistent with known plasmatic pharmacokinetics of THA in AD patients. We conclude that PET imaging with [11C]MTHA is a useful method for assessing the cerebral distribution and kinetics of THA in vivo.

[Neuropsychological aspects of Alzheimer's disease]. / La neuropsychologie de la maladie d'Alzheimer.

This analysis is centered on the study of cognitive disorders in Alzheimer's Disease (AD), mainly for major neuropsychological functions. We insist on the heterogeneity of the clinical picture especially in the early stages of the illness, when deficits of episodic memory and executive functions are prevalent. We consider that studying early stages of the illness is necessary to delineate the diagnostic signs, to validate the new therapeutic experiments, to predict stages of decline.

Memory and depression in Parkinson's disease.

Disorders of learning and memory are a frequent finding in nondemented Parkinson disease (PD) patients. It is not clear to what extent depression, present in at least half the cases of PD, contributes to these disorders. This paper investigates the possible influence of depression on tests of episodic memory in patients with Parkinson's disease (PD). We studied three groups of 11 subjects each (controls, non-depressed PD, mildly to moderately depressed PD). Neuropsychological tests included tests of short and long-term memory in verbal and non-verbal modalities. The two groups of PD patients performed significantly worse than controls on the memory tests, but there were no differences between the depressed and non-depressed PD patients. This lack of influence of depression on neuropsychological performance is compatible with Starkstein's view that cognitive imnpairment is only found beyond a given threshold of depression severity.Copyright Lippincott-Raven Publishers

Frontal lobes pathology and dementia. An appraisal of the contribution of Leonardo Bianchi.

This paper which was inspired by Leonardo Bianchi's work, published in English a hundred years ago, summarizes the main features of frontal dementias, with particular emphasis on Pick's Disease (PiD) and on Frontal Lobe Dementia (FLD). We intend to examine on one hand whether these behavioral changes follow pathology strictly limited to the frontal lobes and on the other hand whether these changes truly constitute a dementia. Currently available data suggest the following conclusions: 1) Lesions to the frontal lobes produce a dementia which is clearly different from the typical picture of Alzheimer's disease and which can be called a behavioral dementia. 2) The pathology of the so-called frontal dementias usually extends beyond the limits of the prefrontal cortex. 3) Executive functions classically thought to be related to frontal lobe structures are in fact associated with structures outside the frontal lobes, particularly in the telencephalic and limbic cortex. These findings in no way diminish the value of the work of Leonardo Bianchi. Rather, they strengthen it. We consider that the work of this great Neuroscientist remains highly relevant and that after 100 years, it still represents the starting basis for further works and ideas.

In vivo imaging of human cerebral acetylcholinesterase.

We report here the first positron emission tomography (PET) images showing the in vivo regional distribution of acetylcholinesterase (AChE) in human brain. The study was carried out in eight healthy human volunteers using as a tracer [11C]-physostigmine ([11C]PHY), an inhibitor of AChE. After intravenous injection of [11C]PHY, radioactivity was rapidly taken up in brain tissue and reached maximal uptake within a few minutes, following a regional pattern mostly related to cerebral perfusion. After the peak, the cerebral radioactivity gradually decreased with a half-life varying from 20 to 35 min, depending on the brain structure. [11C] PHY retention was higher in regions rich in AChE, such as the striatum (half-life, 35 min), than in regions poor in AChE, such as the cerebral cortex (half-life, 20 min). At later times (25-35 min postinjection), the cerebral distribution of [11C]PHY was typical of AChE activity: putamen-caudate > cerebellum > brainstem > thalamus > cerebral cortex, with a striatal to cortex ratio of 2. These results suggest that PET studies with [11C]PHY can provide in vivo brain mapping of human AChE and are promising for the study of changes in AChE levels associated with neurodegenerative diseases.

[Sturge-Weber angiomatosis responsible for hemiplegia without cerebral infarction in term pregnancy]. / Angiomatose de Sturge-Weber responsable d'une hémiplégie sans infarctus cérébral en fin de grossesse.

During the third quarter of her pregnancy, a young woman with Sturge-Weber angiomatosis had a severe right hemiplegia with hemianopia and aphasia, followed 48 hours later by focal seizures. Neuroimaging did not show any cerebral lesion but contrast magnetic resonance imaging revealed a left hemispheric pial angiomatosis. The patient recovered progressively from the third day after a ceasarean. The hemianopia disappeared within 15 days, the hemiplegia within one month and the aphasia greatly improved within 3 months. Ten weeks after the clinical onset, we performed a positron emission tomography study. A decrease from 15 to 40% of the cerebral radioactivity was observed after injection of water (H2(15)O) or fluorodesoxyglucose (18FDG) in the left temporooccipital area adjacent to the meningeal angiomatosis. A chronic and focal olighemia, already reported in Sturge-Weber angiomatosis, might participate in the occurrence of this cortical metabolic depression.